Fable 2: The Bloodstone Banshee Glitch.
If you don't know, this glitch kills the fucking game. Seriously... if you get this glitch you need to start over. From the very beginning. Basically, there is a quest near the end of the game where you need to kill a Banshee on the docks of the town Bloodstone. Simple enough.
However, there is a glitch that means the Banshee takes no damage, no matter what you do to it. So it never dies. And as long as it remains alive it will attack you every time you go near it (which is often as the entrance to Bloodstone leads right to where it is) and you can't do anything else in that town until it is dead.
Oh, and that town is where the final quest is. So you cannot finish the game if you get hit with this glitch.
I'm sure there are work-arounds and I'm pretty sure it has been patched by now in updates, but when I first encountered it I almost just gave up on the game. I didn't though. Not even when I got it twice in a row.